Ponesimod and the Future Questions About S1P Modulator Use

EP: 1.Overviewing Mechanism of Action of S1P-Modulating Treatments

EP: 2.Setting the Stage of S1Ps With Fingolimod

EP: 3.Clinical Pearls on Siponimod

EP: 4.Effectiveness and Advantages of Ozanimod

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EP: 5.Ponesimod and the Future Questions About S1P Modulator Use

EP: 6.Future Directions and Unanswered Questions Regarding S1P Modulator Receptors

Over the years, the multiple sclerosis (MS) neurotherapeutic landscape has rapidly evolved, with new disease-modifying treatments of various novel mechanisms that have improved efficacy and safety. It has been thought that a more tailored approach to treatment will allow for better personalization of drug selection for patients. Sphingosine 1-phosphate (S1P) receptor modulators, one of the newer drug classes, have emerged as a disease-modifying option for MS that has a unique mechanism of action compared with other therapies.

To date, 4 S1P receptor modulators: fingolimod (Gilenya; Novartis), ozanimod (Zeposia; BMS), ponesimod (Ponvory; Janssen), and Siponimod (Mayzent; Novartis), are approved by the FDA and the European Medicines Agency for the treatment of MS. Fingolimod, a nonselective S1P receptor modulator targeting S1P1, S1P3, S1P4, and S1P5, was the first approved therapy in this class, dating back to 2010. This class of medications function by blocking the lymphocytes to egress from lymph notes, leading to a reduction in the number of lymphocytes in the peripheral blood.

As part of a new series, neurologists Patricia Coyle, MD, FAAN, and Adnan Subei, DO, cover the ins and outs of S1P-modulating treatments and their role in the clinical management of MS. The duo give background on how each treatment differs and the advantages each possess, as well as how clinicians have optimized these treatments as experience with them grows.

In this segment, Subei, medical director for the Multiple Sclerosis Program at Neurology Consultants of Dallas, highlighted ponesimod, the most recently approved S1P receptor modulator. He discussed its unique trial design, where it was compared against teriflunomide (Aubagio; Sanofi) and showed a significant reduction in relapse rates. He also noted that while ponesimod is effective, it entered the market later than other similar drugs, which has affected its prominence.

Transcript edited for clarity.

Adnan Subei, DO: Ponesimod is a little bit different because it focuses specifically on the S1P1 receptor as its sole target. The trial design for ponesimod was also unique. The Optimum trial compared ponesimod against teriflunomide as an active comparator, and it met its primary endpoint, showing a 30% reduction in the annualized relapse rate compared to teriflunomide. It also had endpoints regarding combined unique active lesions on MRI. They also included a unique outcome, the Fatigue Symptom Impact Questionnaire, and we saw efficacy there in terms of a decrease in fatigue in patients on ponesimod.

Now, I want to say that we have great data on these selective S1P receptor modulators, and we now have three of them in addition to the original drug, fingolimod. So, at some point, the question becomes, how do these compare? How are they different? We don't have any clinical trials that have put these head-to-head against each other, so we really cannot comment on whether one is superior to the other. That being said, it’s about who came first and who came in last. One of the unfortunate situations with ponesimod is that I think it just came to the market too late. Because of that, it’s not as heavily marketed nowadays since the focus has shifted from that perspective.